WO2014183462A1 - 磷酸/膦酸衍生物及其医药用途 - Google Patents
磷酸/膦酸衍生物及其医药用途 Download PDFInfo
- Publication number
- WO2014183462A1 WO2014183462A1 PCT/CN2014/000302 CN2014000302W WO2014183462A1 WO 2014183462 A1 WO2014183462 A1 WO 2014183462A1 CN 2014000302 W CN2014000302 W CN 2014000302W WO 2014183462 A1 WO2014183462 A1 WO 2014183462A1
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- WO
- WIPO (PCT)
- Prior art keywords
- phosphoric acid
- group
- pharmacologically active
- active molecule
- phosphonic acid
- Prior art date
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- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
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- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000011254 conventional chemotherapy Methods 0.000 description 1
- 125000004122 cyclic group Chemical class 0.000 description 1
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- 125000006612 decyloxy group Chemical group 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- TXFOLHZMICYNRM-UHFFFAOYSA-N dichlorophosphoryloxybenzene Chemical compound ClP(Cl)(=O)OC1=CC=CC=C1 TXFOLHZMICYNRM-UHFFFAOYSA-N 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
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- 238000001035 drying Methods 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
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- AOQKTXNIXJZEJT-UHFFFAOYSA-N formic acid;methanol;hydrate Chemical group O.OC.OC=O AOQKTXNIXJZEJT-UHFFFAOYSA-N 0.000 description 1
- 229960000308 fosfomycin Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 231100000226 haematotoxicity Toxicity 0.000 description 1
- 231100000234 hepatic damage Toxicity 0.000 description 1
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000008818 liver damage Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- FVZVCSNXTFCBQU-UHFFFAOYSA-N phosphanyl Chemical group [PH2] FVZVCSNXTFCBQU-UHFFFAOYSA-N 0.000 description 1
- 125000005328 phosphinyl group Chemical group [PH2](=O)* 0.000 description 1
- 125000005541 phosphonamide group Chemical group 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- GJJLNXZGOBJOFF-ZETCQYMHSA-N propan-2-yl (2s)-2-amino-3-methylbutanoate Chemical compound CC(C)OC(=O)[C@@H](N)C(C)C GJJLNXZGOBJOFF-ZETCQYMHSA-N 0.000 description 1
- KDESEECZHLTGMH-QMMMGPOBSA-N propan-2-yl (2s)-2-amino-4-methylpentanoate Chemical compound CC(C)C[C@H](N)C(=O)OC(C)C KDESEECZHLTGMH-QMMMGPOBSA-N 0.000 description 1
- AHIHJODVQGBOND-UHFFFAOYSA-M propan-2-yl carbonate Chemical compound CC(C)OC([O-])=O AHIHJODVQGBOND-UHFFFAOYSA-M 0.000 description 1
- 125000006308 propyl amino group Chemical group 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- IQFYYKKMVGJFEH-CSMHCCOUSA-N telbivudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1O[C@@H](CO)[C@H](O)C1 IQFYYKKMVGJFEH-CSMHCCOUSA-N 0.000 description 1
- 229960005311 telbivudine Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- 210000003934 vacuole Anatomy 0.000 description 1
- 230000005570 vertical transmission Effects 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4062—Esters of acids containing the structure -C(=X)-P(=X)(XR)2 or NC-P(=X)(XR)2, (X = O, S, Se)
- C07F9/4065—Esters of acids containing the structure -C(=X)-P(=X)(XR)2, (X = O, S, Se)
-
- C—CHEMISTRY; METALLURGY
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4071—Esters thereof the ester moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4087—Esters with arylalkanols
-
- C—CHEMISTRY; METALLURGY
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6524—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having four or more nitrogen atoms as the only ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
- C07F9/65517—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring condensed with carbocyclic rings or carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
- C07F9/657181—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
-
- C—CHEMISTRY; METALLURGY
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/6574—Esters of oxyacids of phosphorus
- C07F9/65742—Esters of oxyacids of phosphorus non-condensed with carbocyclic rings or heterocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H19/207—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
Definitions
- the present invention relates to novel liver-targeted prodrug derivatives containing a pharmacologically active molecule of a phosphate or phosphonate group in a molecule, and non-toxic pharmaceutically acceptable salts, hydrates or solvates thereof, and derivatives derived therefrom And a non-toxic pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient and a pharmaceutical composition formed by a suitable excipient, and the prodrug derivative and its non-toxic pharmaceutically acceptable
- the liver is a sputum organ of viral hepatitis, cirrhosis, and liver cancer, and is also the main organ of glycolipid metabolism. Research on treatment techniques, treatments, and therapeutic drugs for these diseases has made important progress in the past decade, but it is far from meeting clinical needs.
- interferon is unstable and has side effects; anti-hepatitis B virus lamivudine is susceptible to drug resistance, adefovir dipivoxil has dose-limiting renal toxicity; and the only small molecule anti-hepatitis C Long-term use of the viral drug ribavirin can cause severe hematological toxicity.
- conventional chemotherapy drugs have large side effects. There are no safe and effective drugs for liver fibrosis and cirrhosis. For diabetes and hyperlipidemia, clinically new and more effective treatments are urgently needed.
- Nucleoside phosphate/phosphonic acid is an important component of antiviral drugs.
- Nucleoside analogs such as lamivudine, telbivudine, entecavir, ribavirin, and PSI-6130 all form pharmacologically active nucleotide analogs by phosphorylation, exerting antiviral effects.
- Adefovir PMEA
- PMPA tenofovir
- PMPDAP PMPDAP
- HBV-active acyclic nucleoside phosphonate analog HBV-active acyclic nucleoside phosphonate analog.
- MB05032 is a phosphonic acid fructose 1,6-bisphosphatase inhibitor with hypoglycemic action
- MB07344 is a phosphonic acid thyroid receptor agonist with lipid lowering action.
- MB05032 since the pharmacologically active molecule containing a phosphoric acid or a phosphonic acid group is difficult to permeate through the cell membrane due to the strong polarity of the phosphoric acid or phosphonic acid group, the bioavailability of oral administration is low, and it is difficult to achieve an effective therapeutic concentration. Therefore, research and development of safe and effective prodrugs containing pharmacologically active molecules of phosphoric acid or phosphonic acid groups is the key to the development of such drugs.
- Adefovir dipivoxil and LB-80380 are prodrugs of pivalic acid, and tenofovir is a prodrug of isopropyl carbonate. Adefovir dipivoxil and tenofovir are the most widely used clinically
- Adefovir valerate LB-80380 tenofovir pirfenate LB-80380 tenofovir pirfenate
- adefovir valerate, LB-80380 and tenofovir pirfen ester have poor chemical stability, and the drug substance and preparation pair Temperature and humidity are sensitive, easy to decompose to form a monoester that the human body can not absorb; its metabolite formaldehyde is toxic to human body; and because it is unstable in the gastrointestinal tract, it is easily hydrolyzed to form a strong acid phosphonic acid compound, which has Irritating.
- LB-80380 enters the body, and the pivalic acid produced by hydrolysis is not easily metabolized and has certain side effects.
- MCC-478 is a tricyclic ethanol ester with acyclic nucleotides resistant to hepatitis B virus and has good chemical stability. MCC-478 enters the body and releases free acid (602076) to exert antiviral effect; however, the phase I clinical pharmacokinetic study shows that the main metabolite of MCC-478 in human body is nucleotide monoester (602074) The free acid 602076 has a plasma concentration of only 1/10 of the monoester 602074 (Clark Chan, et al.
- SATE S-acetylethyl ester
- SATE S-acetylthioethyl ester
- CGS25463 and CGS26393 are bisphenol ester prodrugs of phosphonic acid derivatives that release active phosphonic acid drugs into the body:
- PSI-7977 and INX-08189 are prodrugs of phosphoramidate phenolic esters and phosphoramidate naphthol esters, respectively, having anti-HIV activity nucleotides, which release nucleoside monophosphate derivatives and further convert to triphosphate products after entering the body. , play the role of anti-HCV:
- CGS25463> CGS26393> PSI-7977 and INX-08189 will produce highly toxic phenolic substances when they enter the body.
- Pradefovir, MB07811 and MB07133 are prodrugs of anti-hepatitis B drug PMEA, thyroid receptor agonist MB07344 and benzo-substituted cyclic phosphonate of antitumor drug cytarabine; these prodrugs have good chemical stability, Stable in the gastrointestinal tract and blood, and can be selectively oxidized by the cytochrome P450 enzyme in the liver, and the active drug PMEA, MB07344 or cytarabine is released in the liver to exert anti-HBV action, lipid-lowering effect or Anti-liver cancer effect:
- Pradefovir, MB07811 and MB07133 enter the body they produce highly carcinogenic metabolic intermediates that are carcinogenic.
- the present invention provides a phosphoric acid/phosphonic acid derivative of the formula I: Where 1 ⁇ or 1 2 represents the following structure:
- Q1 represents an ester derivative of an L-amino acid, wherein R 3 is an alkyl group or a cycloalkyl group having 1 to 6 carbon atoms, R 4 is H or an alkyl group having 1 to 6 carbon atoms; and Q2 represents a messy group substituted with a hydroxyl group.
- a dioxane derivative Q3 represents a hydroxy-substituted benzodioxolane derivative; ⁇ or the same or different, but at least one of them
- HO—P—D is Q2 or Q3; D represents the residue of a pharmacologically active molecule containing a phosphoric acid/phosphonate group, that is, ⁇ represents a pharmacologically active molecule containing a phosphoric acid/phosphonate group; when R] is different, and 1 ⁇
- the configuration of the P atom connected to 1 2 is R type or S type.
- the inventors have found through extensive research that the phosphoric acid/phosphonic acid derivative represented by Formula I has higher biological activity and better biosafety than the prior art; the inventors have also unexpectedly discovered that the target compound is It is stable in the gastrointestinal tract and blood, and can fully release active substances in the liver, and has good liver targeting; the inventors have more unexpectedly found that the target compound represented by Formula I has liver protection after oral administration. It can inhibit liver damage caused by hepatitis virus and rapidly reduce the increase of transaminase caused by hepatitis virus.
- liver metabolic disorders such as hyperlipemia and hyperglycemia.
- compositions comprising the phosphoric acid/phosphonic acid derivative of the formula I and a non-toxic pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable excipient; these pharmaceutical compositions may be tablets , such as immediate release tablets, sustained release tablets, controlled release tablets, film-coated tablets, sugar-coated tablets, buccal tablets, sublingual tablets, etc.; capsules such as hard gelatin, soft gelatin, etc.; injections such as sterile Or aqueous injection containing bacteriostatic agent Injection, oily injection, freeze-dried powder injection, injection ball, etc.
- tablets such as immediate release tablets, sustained release tablets, controlled release tablets, film-coated tablets, sugar-coated tablets, buccal tablets, sublingual tablets, etc.
- capsules such as hard gelatin, soft gelatin, etc.
- injections such as sterile Or aqueous injection containing bacteriostatic agent Injection, oily injection, freeze-dried powder injection, injection ball, etc.
- the phosphoric acid/phosphonic acid derivatives of formula I can be prepared according to the following synthetic route:
- the phosphonate target compound in which R 2 is both Q2 or Q3 can be prepared according to the synthetic route 1:
- the PMEA is condensed with a 5-hydroxybenzodioxol-free hydroxyl group under the action of dicyclohexylcarbodiimide to obtain the target compound.
- Route 2 Taking the preparation of a 5-hydroxybenzodioxy acyclic phosphate derivative of acyclovir as an example, a phthalate ester compound in which R and R 2 are both Q2 or Q3 can be prepared according to the synthetic route II. :
- Acyclovir reacts with trichlorophosphonium to form a phosphorus oxychloride intermediate ⁇ 1 ⁇ , which reacts with 5-hydroxybenzodioxane to obtain the target compound.
- Route 3 Take the preparation of a phosphonium amide monoester derivative as an example, ! ⁇ , R 2 is Q2 Or the phosphonamide monoester target compound of Q3 can be prepared according to the synthetic route III:
- PMEA is first condensed with a 5-hydroxybenzodioxy acyclic hydroxy group under the action of dicyclohexylcarbodiimide to obtain a monoester derivative III, III, which is reacted with thionyl chloride to form a phosphonochloromonoester.
- Body IV! IVi reacts with an amino acid ester to obtain a target compound.
- Route 4 Taking the preparation of a phosphoramide monoester derivative of acyclovir as an example, a phosphoramide monoester target compound having Q1, R 2 of 02 or Q3 can be prepared according to the synthetic route IV:
- Nuclear magnetic resonance ⁇ (ppm, DMSO-d6): 7.68 (d, IH); 7.25-7.30 (m, 7H); 6.23 (t, IH); 6.11 (m, IH); 5.72 (d, 1H); 5.35 (t , 1 H); 4.27 (m, 2H); 3.88 (m, IH); 3.58 (s , 3H); 3.42 ( q, IH); 3.05 (m, 2H); 1.21 (d, 3H).
- GS-7340 Add 4,6 g of 9-[(R)-2-(phosphonomethoxy)propyl]-adenine (PMPA), 9.6 g of phenol to 50 ml of N-methylpyrrolidone, heat to At 85 ° C, 6.3 ml of triethylamine was added. 13.4 g of DCC was slowly added under stirring, and the mixture was stirred under heating at 100 ° C overnight, and after cooling, 30 ml of water was added. The organic layer was separated, and the filtrate was combined, evaporated, evaporated, evaporated, evaporated, evaporated. The aqueous solution was adjusted to pH 3.1 with 3 7 % hydrochloric acid, and a solid was precipitated. The solid was collected by filtration, washed with stirring with 50 ml of methanol, filtered, and dried in vacuo to afford 7.2 g of phenol monoester derivative of PMPA.
- PMPA 9-[(R)-2-(phosphonomethoxy)propyl]
- the column was Diacel's Chiralpak AS, and the mobile phase was acetonitrile solution containing 20% isopropanol at a flow rate of 8 ml/min. The two components were evaporated to dryness under reduced pressure to give 0.21 g of PSI-7977.
- Example 1 Reference Example 1, using 4-hydroxybenzaldehyde instead of 5-hydroxybenzo [1,4] dioxane, and [1, 3] dioxolane, and PMEA condensation, separation and the like treated Purification gave the title compound 13 in a yield of 19%.
- Nuclear magnetic resonance ⁇ (ppm, DMSO-d6): 8.16 (s, 1H); 8.12 (s, 1H); 7.33 (b, 2H); 6.58-6.62 (t, 2H); 6.51-6.53 (d, 2H) 6.41-6.43(d, 2H); 4.35-4.33(t, 2H); 4.20-4.24(m, 8H); 3.92-3.90(t, 2H); 3.79-3.77(d, 2H).
- Example 4 9-[ [[bis-((Benzo[1,4]dioxo-6-yl)-oxy)-phosphono]-decyloxy]-ethyl] - adenine (L) Preparation
- Example 13 2 -Amino-6-decyloxy-9-[ [[bis-((stano[1,3]dioxopenta-5-yl)-oxy)-oxy]-ethoxy) Preparation of -methyl] - ⁇ (In )
- Example 1 1 Refer to the method of Example 1 1 to replace the reaction of acyclovir with phosphorus oxychloride with 2-amino-6-methoxy-9-[(2-hydroxyethoxy)-methyl]-indole Treated by a similar method and isolated and purified to give 2 -amino-6-methoxy-9-[( 2 -dichlorophosphoryloxy-ethoxy)-methyl]-indole (11 2 ).
- lamivudine was used instead of acyclovir to react with phosphorus oxychloride, and treated by a similar method and isolated and purified to obtain lamivudine dichlorophosphate derivative ⁇ 3 .
- the 5-hydroxybenzo[1,3]dioxolane was reacted with 11 3 and treated in a similar manner and purified to give the title compound 1, 4, yield 12.0%.
- Nuclear magnetic resonance spectroscopy ppm, DMSO-d6): 7.71 (d, 1H);
- Example 15 9-[(lS, 3R,4S)-4-hydroxy-3-(bis((benzo[1,3]dioxopenta-5-yl)-oxy)-phosphoryl) -Oxoindolyl)-2-indolylcyclopentyl]-guanine (1 15 )
- entecavir was used in place of acyclovir to react with phosphorus oxychloride, treated by a similar method, and isolated and purified to obtain a dichlorophosphate derivative ⁇ 4 of entecavir.
- ⁇ 2 was used instead of III, It is reacted with thionyl chloride, treated by a similar method and isolated and purified to obtain 9-[(R)-2-[(((benzo[1,3]dioxopenta-4-yl)-oxy)- Monochloro-phosphono]-decyloxy]-propyl]-adenine ( ⁇ .
- ⁇ 9-[(R)-2-[(((benzo[1,3]dioxopenta-4-yl)-oxy)- Monochloro-phosphono]-decyloxy]-propyl]-adenine
- replace IV with IV 2 , react with L-alanine isopropyl ester, and treat it in a similar manner. And separation and purification, obtained 1 24 , yield 13.7%, nuclear magnetic resonance spectrum ⁇ (ppm, DMSO-d6):
- 2-amino-6-(4-methoxyphenyl)--9-[(phosphono-methoxy)-ethyl]-indole was used in place of PMPA, and 5-hydroxyl group.
- Benzo[1,3]dioxolane reaction treated by similar methods and isolated and purified to give 2-amino-6-(4-methoxyphenylthio)-9-[[[(((benzo[ 1,3]dioxapenta-5-yl)-oxy)-phosphono]-methoxy]-ethyl]-indole ( ⁇ 3 ).
- hydrazine 3 was used instead of III, and reacted with thionyl chloride, treated by a similar method and isolated and purified to obtain 2-amino-6-(4-decyloxyphenylthio)-9-[[ [((Benzo[1,3]dioxopenta-5-yl)-oxy)-monochlorophosphonyl]-decyloxy]-ethyl]-indole (IV 3 ).
- Example 19 Referring to the method of Example 19, IV 3 was used instead of IV, and reacted with L-alanine isopropyl ester, treated by a similar method and isolated and purified to obtain 1 26 , a yield of 1 U. 4%, and nuclear magnetic resonance hydroquinone ⁇ ( Ppm, DMSO-d6 ):
- acyclovir 0.22 g was dissolved in 50 ml of TH and then 7 ml of pyridine was added, and 1 ml of a 1 M solution of monobutylmagnesium chloride in THF was added thereto, and the mixture was stirred for 0.5 h, and 2 ml of a 1 M v 3 THF solution was added thereto with stirring, followed by stirring for 2 h.
- Example 27 replacing L-alanine isopropion with L-alanine ethyl ester
- the reaction of dioxopenta-5-yl)-oxy-phosphonium oxychloride is carried out by a similar method, and is isolated and purified to obtain intermediate V 5 of phosphoramide, which is directly used in the next step.
- V 5 was reacted with ⁇ -D-2'-deoxy-2,-a-fluoro-2'- ⁇ -C-methyluridine, and treated by a similar method, and separated and purified to obtain a target.
- Compound I 3Q yield 13.5%.
- Nuclear magnetic resonance spectroscopy (ppm, DMSO-d6): 11.37 (s, IH); 7.82 (d, IH); 6.77-6.75 (d,
- the color column was Diacel, s Chiralpak AS, and the mobile phase was acetonitrile solution containing 20% isopropanol at a flow rate of 8 ml/min.
- the first main peak was evaporated to dryness under reduced pressure to give I 31 -a 0.28 g.
- the second main peak was collected and evaporated to dryness to give I 31 - b 0.23 g.
- the residue was subjected to silica gel column chromatography eluting eluting eluting eluting eluting The residue was dissolved in acetonitrile containing 20% isopropanol and chromatographed by preparative chromatography.
- the column was Diacel's Chiralpak AS and the mobile phase was acetonitrile solution containing 20% isopropanol.
- Example 39 9- [ (IS, 3R, 4S) - 4-hydroxy-3-( [((phenyl)[1,3]dioxopenta-4-yl)-oxy)-1-isopropoxy Carboethylethylamino-phosphoryl)-oxinyl]-2-indenylcyclopentyl]-guanine 39
- I 39 -a I 39 -b Add 15.3 g of phosphorus oxychloride and 13.8 g of 4-hydroxybenzodioxane to a solution of 250 ml of anhydrous ether under argon and cool to -78 ° : 13.4 ml of triethylamine was added dropwise, and after the addition, the mixture was stirred at -78 ° C for 30 minutes, and then stirred at room temperature overnight. Filtration and evaporation of the filtrate under reduced pressure gave benzo[1,3]dioxapenta-4-yl)-oxy-dichlorophosphon
- the entecavir was dissolved 8.25g 80ml THF, followed by addition of 9g N- methylimidazole, was added 10.5g V 7 was dissolved in 50ml THF. It was stirred overnight at room temperature, and the filtrate was evaporated to dryness vacuo. The residue was subjected to silica gel column chromatography eluting eluting The residue was dissolved in acetonitrile containing 20% isopropanol and chromatographically separated by preparative chromatography. The chromatographic column was Diacel 's Chiralpak AS, and the mobile phase was acetonitrile solution containing 20% isopropanol at a flow rate of 8 ml/min. A main peak was evaporated to dryness under reduced pressure to give I 39 -a 0.27 g. The second main peak was collected and evaporated to dryness to give I 39 - b 0.20 g.
- the column was Diacel's Chiralpak AS, and the mobile phase was acetonitrile solution containing 20% isopropanol at a flow rate of 8 ml/min. a peak, evaporated to dryness under reduced pressure to give I 4 () -a 0.22g; second major peak was collected, evaporated to dryness under reduced pressure to give I 40 -b 0.24g.
- V 6 was used instead of V 3 to react with acyclovir, treated by a similar method, and isolated and purified to give the title compound 1 41 , yield 23.3%. 7.83 (s, 1H); 6.77-6.75(d, 1H); 6.68(s, 1H); 6.5 (bs, 2H); 6.49-6.47(4 1H); 6.00-5.93 (m, 3H); 5.36 (s 2, 2, 3, 3, 3, 3, 3, 3
- Example 19 ⁇ 4 was used instead of III, and reacted with thionyl chloride, treated by a similar method and isolated and purified to obtain [( 3 , 5 - dimethyl - 4 - (4' - hydroxy - 3 ' - Isopropylbenzyl)phenoxy)-methyl]-phosphonic acid-(benzo[1,3]dioxopenta-5-yl)-monoester monophosphoryl chloride (IV 4 ).
- IV 4 was used instead of IV, and reacted with L-alanine isopropyl ester, treated by a similar method and isolated and purified to give the title compound 1 42 in a yield of 15.5%.
- Hep G 2.2.15 cells were seeded in % well plates, the number of cells was 3.5 x 10 4 cultures, and the cells were incubated in a C0 2 incubator until the cell density reached 80%.
- the culture solution was discarded and new drugs containing different concentrations of the drug to be tested were added.
- the culture solution was set up with 3 parallel holes; the culture solution was changed every 2 days. On the 10th day after administration, 100 ⁇ L of the supernatant was taken, and the content of HBV DNA was determined by quantitative PCR to calculate IC 5 . value.
- Table 1 In vitro anti-HBV activity screening results
- Hep G 2.2.15 cells were seeded in % well plates, the number of cells was 5.5 x 10 4 , and the culture was continued for 3 days. New culture medium containing different concentrations of drugs was added, and 3 parallel holes were set. On the 3rd day after administration, Add MT to 7.5 mg/ml, continue to culture for 2 hours, discard the supernatant, add 10% Tween X-100 isopropyl alcohol, 120 ⁇ l/well, add 0.4 ⁇ l/well, and measure 540 nm by enzyme-linked instrument. For the absorption, calculate 50% CC 5 . value. The results are shown in Table 2.
- Example 46 Liver targeting evaluation The high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was used to determine the active drug (free phosphonic acid or in blood and liver tissue at different time points after intragastric administration of the target compound mice. The concentration/content of free phosphoric acid was calculated, and the liver/blood drug concentration ratio was calculated to compare liver targeting.
- HPLC-MS/MS high performance liquid chromatography-tandem mass spectrometry
- the column is a Discovery ODS column (250 mm X 4.6 mm, 5 ⁇ m), a CI 8 guard column (4 mm X 3.0 mm), and the mobile phase is methanol-water-formic acid (10-30:90-70:0.5, V) /V/V), flow rate OJ ml/min; injection volume 20 ⁇ L; column temperature is room temperature.
- Animal experiment is a Discovery ODS column (250 mm X 4.6 mm, 5 ⁇ m), a CI 8 guard column (4 mm X 3.0 mm), and the mobile phase is methanol-water-formic acid (10-30:90-70:0.5, V) /V/V), flow rate OJ ml/min; injection volume 20 ⁇ L; column temperature is room temperature. Animal experiment
- mice male, fasted for 16 h, were randomly divided into 3 groups, 3 rats in each group, respectively, given intragastric administration of fosfomycin (200 mg / kg) or an equimolar dose of the target compound.
- the suspension of sodium cellulose is centrifuged at 1 hour and 6 hours after administration to obtain serum, and the liver tissue is taken to prepare a homogenate, and the supernatant is centrifuged; the active drug in the blood and liver tissue (free phosphonic acid or Free Phosphoric acid concentration/content, calculate the liver/blood drug concentration ratio.
- Table 3 The results are shown in Table 3.
- Kunming mice (20 g) were randomly divided into groups (8 in each group). 0.2 mmol of the test compound was orally administered; after administration for 1 h, a peanut oil solution (10 mL/k ⁇ ) of 0.1% CC1 4 was injected subcutaneously to prepare a liver injury model; physiological saline was injected as a normal control group. Twelve hours after modeling, 0.2 mmol of the test compound was orally administered again. 24 hours after the second administration, blood samples were taken for serum determination of ALT, and ASTo results are shown in Table 4.
- Kunming mice (20 g) were randomized (8 in each group). 0.2 mmol of the test compound was orally administered; 2 h after administration, a liver injury model was prepared by intraperitoneal injection of D-galactosamine at a dose of 750 mg/kg, and physiological saline was subcutaneously administered as a normal control group. After 12 h of modeling, 0.2 mmol of the test compound was orally administered again. 24 hours after the second administration, blood samples were taken and serum samples were taken to determine ALT and AST. The results are shown in Table 5.
- Larvae with vertical transmission infection and positive DHBV DNA detection were randomly divided into groups of 5 each. Water and different doses of the test compound were administered by intragastric administration once a day for 14 days. Blood was collected venous before administration, 14 days after administration, and 7 days after drug withdrawal. The serum DHBV DNA content was determined by external standard TaqMan real-time fluorescent PCR method, and the inhibition rate was compared with the solvent group. The results are shown in Table 6:
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2014
- 2014-03-20 EP EP14798157.5A patent/EP2998307B1/en active Active
- 2014-03-20 AU AU2014268040A patent/AU2014268040B2/en active Active
- 2014-03-20 WO PCT/CN2014/000302 patent/WO2014183462A1/zh active Application Filing
- 2014-03-20 JP JP2016513204A patent/JP2016520070A/ja active Pending
- 2014-03-20 US US14/890,973 patent/US20160115186A1/en not_active Abandoned
- 2014-03-20 KR KR1020157035435A patent/KR20160007651A/ko not_active Application Discontinuation
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Cited By (7)
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US9908908B2 (en) | 2012-08-30 | 2018-03-06 | Jiangsu Hansoh Pharmaceutical Co., Ltd. | Tenofovir prodrug and pharmaceutical uses thereof |
WO2015101183A1 (zh) * | 2014-01-02 | 2015-07-09 | 江苏豪森药业股份有限公司 | 尿嘧啶核苷酸类似物及其制备方法和应用 |
CN105829334A (zh) * | 2014-01-02 | 2016-08-03 | 江苏豪森药业集团有限公司 | 尿嘧啶核苷酸类似物及其制备方法和应用 |
CN105829334B (zh) * | 2014-01-02 | 2019-03-08 | 江苏豪森药业集团有限公司 | 尿嘧啶核苷酸类似物及其制备方法和应用 |
WO2021032218A1 (zh) * | 2019-08-19 | 2021-02-25 | 苏州闻天医药科技有限公司 | 一种并环THRβ受体激动剂化合物及其制备方法和用途 |
GB2603330A (en) * | 2019-08-19 | 2022-08-03 | Hepagene Therapeutics Hk Ltd | Heterocyclic THR-# receptor agonist compound and preparation method and use therefor |
GB2603330B (en) * | 2019-08-19 | 2023-08-09 | Hepagene Therapeutics Hk Ltd | Heterocyclic THR-B receptor agonist compound and preparation method and use therefor |
Also Published As
Publication number | Publication date |
---|---|
KR20160007651A (ko) | 2016-01-20 |
EP2998307A1 (en) | 2016-03-23 |
AU2014268040B2 (en) | 2017-02-02 |
CN104151360A (zh) | 2014-11-19 |
EP2998307B1 (en) | 2018-10-31 |
EP2998307A4 (en) | 2017-02-15 |
US20160115186A1 (en) | 2016-04-28 |
CN110156838A (zh) | 2019-08-23 |
JP2016520070A (ja) | 2016-07-11 |
CN104151360B (zh) | 2019-02-22 |
AU2014268040A1 (en) | 2016-01-07 |
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